Selective Covalent Targeting of Anti-apoptotic BFL-1 by a Sulfonium-Tethered Peptide.
Chembiochem
; 22(2): 340-344, 2021 01 15.
Article
em En
| MEDLINE
| ID: mdl-32790056
Anti-apoptotic B cell lymphoma 2 (BCL-2) family proteins are proven targets for human cancers. Targeting the BH3-binding pockets of these anti-apoptotic proteins could reactivate apoptosis in BCL-2-depedent cancers. BFL-1 is a BCL-2 family protein overexpressed in various chemoresistant cancers. A unique cysteine at the binding interface of the BH3 and BFL-1 was previously proven to be an intriguing targeting site to irreversibly inhibit BFL-1 functions with stabilized cyclic peptide bearing a covalent warhead. Recently, we developed a sulfonium-tethered peptide cyclization strategy to construct peptide ligands that could selectively and efficiently react with the cysteine(s) of target proteins near the interacting interface. Using this method, we constructed a BFL-1 peptide inhibitor, B4-MC, that could selectively conjugate with BFL-1 both inâ
vitro and in cell. B4-MC showed good cellular uptake, colocalized with BFL-1 on mitochondria, and showed obvious growth inhibition of BFL-1 over-expressed cancer cell lines.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Compostos de Sulfidrila
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Proteínas Proto-Oncogênicas c-bcl-2
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Proteínas Reguladoras de Apoptose
Limite:
Humans
Idioma:
En
Revista:
Chembiochem
Ano de publicação:
2021
Tipo de documento:
Article